Inflammatory manifestations of experimental lymphatic insufficiency
2006; 3 (7): 1114-1139
An experimental model for the study of lymphedema and its response to therapeutic lymphangiogenesis
2006; 20 (6): 363-370
Sustained lymph stagnation engenders a pathological response that is complex and not well characterized. Tissue inflammation in lymphedema may reflect either an active or passive consequence of impaired immune traffic.We studied an experimental model of acute post-surgical lymphedema in the tails of female hairless, immunocompetent SKH-1 mice. We performed in vivo imaging of impaired immune traffic in experimental, murine acquired lymphatic insufficiency. We demonstrated impaired mobilization of immunocompetent cells from the lymphedematous region. These findings correlated with histopathological alterations and large-scale transcriptional profiling results. We found intense inflammatory changes in the dermis and the subdermis. The molecular pattern in the RNA extracted from the whole tissue was dominated by the upregulation of genes related to acute inflammation, immune response, complement activation, wound healing, fibrosis, and oxidative stress response.We have characterized a mouse model of acute, acquired lymphedema using in vivo functional imaging and histopathological correlation. The model closely simulates the volume response, histopathology, and lymphoscintigraphic characteristics of human acquired lymphedema, and the response is accompanied by an increase in the number and size of microlymphatic structures in the lymphedematous cutaneous tissues. Molecular characterization through clustering of genes with known functions provides insights into processes and signaling pathways that compose the acute tissue response to lymph stagnation. Further study of genes identified through this effort will continue to elucidate the molecular mechanisms and lead to potential therapeutic strategies for lymphatic vascular insufficiency.
View details for DOI 10.1371/journal.pmed.0030254
View details for PubMedID 16834456
The lymphatic biology of Kaposi's sarcoma.
Lymphatic research and biology
2005; 3 (1): 25-35
Evaluation of the efficacy of molecular treatment strategies for lymphatic vascular insufficiency requires a suitable preclinical animal model. Ideally, the model should closely replicate the untreated human disease in its pathogenesis and pathological expression.We have undertaken a study of the time course of the development and resolution of acquired, experimental lymphedema and of its responses to vascular endothelial growth factor (VEGF)-C lymphangiogenesis in the mouse tail model.We provoked post-surgical lymphedema in the mouse tail model and assessed the effects of exogenously administered human recombinant VEGF-C. Quantitative assessment of immune traffic function was performed through sequential in vivo bioluminescent imaging.In untreated lymphedema, tail edema was sustained until day 21. Exogenous administration of human recombinant VEGF-C produced a significant decrease in volume. Untreated lymphedema in the mouse tail model was characterized by the presence of dilated cutaneous lymphatics, marked acute inflammatory changes, and hypercellularity; VEGF-C produced a substantial reversion to the normal pattern, with notable regression in the size and number of cutaneous lymphatic vessels that express lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1). In vivo imaging confirmed the presence of an impairment of immune traffic in lymphedema that was ameliorated after VEGF-C administration.The post-surgical murine tail model of lymphedema closely simulates attributes of human lymphedema and provides the requisite sensitivity to detect therapeutically induced functional and structural alterations. It can, therefore, be used as an investigative platform to assess mechanisms of disease and its responses to candidate therapies, such as therapeutic lymphangiogenesis.
View details for PubMedID 17176124